Outcomes of adult patients with relapsed/refractory <scp>CRLF2</scp> rearranged B‐cell acute lymphoblastic leukemia
Authors: Sai Prasad Desikan, Jayastu Senapati, Elias Jabbour, Tareq Abuasab, Nicholas Short, Guilin Tang, Sa Wang, Partow Kebriaei, Tapan Kadia, Gautam Borthakur, Farhad Ravandi, Kathryn Roberts, Charles Mullighan, Marina Konopleva, Hagop Kantarjian, Nitin Jain
Journal: American Journal of Hematology (2023)

Philadelphia chromosome-like (Ph-like) B-cell acute lymphoblastic leukemia (B-ALL) is characterized by a gene expression profile that is similar to Philadelphia chromosome-positive (Ph+) B-ALL but without the presence of BCR::ABL1 translocation.1-4 Among adult patients with Ph-like ALL, those with CRLF2 overexpression tend to have worse outcomes after treatment with conventional chemotherapy.5 As patients with CRLF2-rearranged B-ALL have activation of the JAK/STAT pathway, ruxolitinib has been investigated in combination with conventional chemotherapy with limited clinical activity.6 Given the dismal prognosis of patients with CRLF2-rearranged B-ALL, the outcomes of these patients are important to study, especially in the context of novel B-cell targeting therapies such as inotuzumab ozogamicin, blinatumomab, and chimeric antigen receptor T (CAR T) cell therapy. We retrospectively analyzed the treatment outcomes of patients with relapsed and/or refractory (R/R) CRLF2-rearranged B-ALL treated at our institution [MD Anderson Cancer Center (MDACC), Houston, TX]. CRLF2 expression was assessed by flow cytometry and/or fluorescence in-situ hybridization (FISH) and/or gene expression profile. We previously reported 100% concordance between flow cytometry for CRLF2 expression and FISH for CRLF2 rearrangement in patients with B-ALL.7 We assessed prior treatment details, disease characteristics including cytogenetics and JAK2 mutation status, salvage therapy received at our institution, response, and survival outcomes. The timepoint of study entry of patients in this retrospective analysis was the time of first therapy received at our institution with relapsed and/or refractory disease. For patients who had received their frontline therapy at our institution, we assessed outcomes from the first salvage regimen for the first relapse or primary refractory disease. For patients who presented to our institution with R/R disease after prior therapy at an outside hospital, study entry was at the time of first therapy received at MDACC. Relapse-free survival (RFS) was calculated from response to salvage therapy to subsequent relapse or death; overall survival (OS) was calculated from study entry to death. Kaplan Meier method was used for survival analysis and GraphPad Prism version 9.3.1 for Windows, GraphPad Software, San Diego, California United States, was used for statistical analysis. From November 2001 to March 2021, 69 patients with R/R CRLF2-rearranged B-ALL who received treatment at our center were identified. A total of 41 patients were identified on the basis of CRLF2 overexpression by CRLF2 flow cytometry of which 26 patients had a concomitant CRLF2 FISH performed, and all had CRLF2 rearrangement (18 IGH, 6 P2RY8, and 2 with unknown partner gene). The remaining 28 patients were identified by gene expression profile (St. Jude Children's Research Hospital). Seventy-one percent of patients were male and 70% of all patients identified as Hispanic. The median age at presentation was 36 years (range, 18–72 years) and the median number of prior lines of therapy was 1 (range, 1–5). Baseline patient characteristics are described in Table S1. Fifty-one patients (74%) had received only chemotherapy prior to study entry; the remaining 18 patients (26%) received targeted therapy (inotuzumab ozogamicin, blinatumomab, and/or CAR T cell therapy) prior to study entry. Nine patients (9/69, 13%) had a prior allogeneic stem cell transplantation (allo-SCT). The median time to study entry from initial diagnosis of B-ALL was 15 months (range, 0.5–280 months). Of the 61 patients who were assessed for JAK2 mutation, 24 (39%) had a mutation. Patients were divided into two cohorts based on their first salvage therapy at MDACC: (1) targeted therapy cohort (T; patients who received inotuzumab ozogamicin and/or blinatumomab, and/or CAR T cell therapy, n = 28) with or without a chemotherapy backbone; (2) conventional chemotherapy cohort (C; n = 41). Treatment regimens for both cohorts are detailed in Table S2. The median age in the T and C cohorts was 39 years and 35 years, respectively. The two groups were well balanced for age, prior lines of therapy and prior allo-SCT; however, more patients in the C cohort had JAK2 mutation than in the T cohort (50% vs. 22% in the C and T cohorts, respectively) and a higher proportion of patients in the T cohort had received prior targeted therapy (32% vs. 21% in the T and C cohorts, respectively). The complete remission/complete remission with incomplete count recovery (CR/CRi) rate was 43% for the whole group [15 of 28 patients (54%) in the T cohort and 15 of 41 patients (37%) in the C cohort, p = .21]. Twelve of 15 (80%) responding patients in the T cohort and 12 of 14 (85%) responding patients in the C cohort evaluated for measurable residual disease (MRD) status were MRD negative. The median number of cycles to respond for the entire cohort was 1 (range, 1–3). At a median follow-up of 46 months for the whole cohort from study entry, the median OS was 9.2 months; the median OS among the responding patients was 24.4 months, as detailed in Figure S1. The median OS for the targeted therapy group was 11.8 versus 5.8 months for the conventional chemotherapy group (p log rank = 0.11) (Figure 1). We further analyzed the survival outcomes based on the JAK2 mutation status. Overall, the median OS was shorter in patients with JAK2 mutations (JAK2mut) versus JAK2 wild-type (JAK2WT) patients (5.8 vs. 10.5 months, p log rank = 0.16), as detailed in Figure S2. Although the absolute numbers of patients were small, the median survival of the 5 JAK2mut patients in the T cohort was 9.3 months compared to 11.8 months in the 19 JAK2WT patients (Figure S3). Twenty-one patients underwent allo-SCT at a median of 3.4 months after study entry: 10 patients in the T cohort and 11 patients in the C cohort (Table S3). Only one of the 21 transplanted patients had undergone a prior allo-SCT. Six transplanted patients had a JAK2 mutation, one in the T arm and 5 in the C arm. The 1-year OS for all the transplanted patients was 67% (Figure S4). We report here the outcomes of a large cohort of patients with R/R CRLF2-rearranged B-ALL. We highlight differences in the outcomes when patients received B-cell-directed targeted therapies (such as inotuzumab ozogamicin, blinatumomab, CAR T) versus conventional chemotherapy regimens without targeted therapies. Patients who received some form of B-cell-directed targeted regimen as part of the salvage therapy at study entry had higher response rates and numerically higher OS. Though the differences were not statistically significant, this was likely due to the small patient numbers in each treatment cohort. Treatment options in the R/R B-ALL include allo-SCT at the time of remission. Several of the patients who achieved remission were able to proceed to an allo-SCT in remission with favorable long-term survival. As a result of higher rates of remission, the use of targeted regimens might enable more patients to proceed to an allo-SCT in remission. Our study had some limitations, the most important of which was the different time points during the salvage therapy at which patients were captured in the study. The non-uniform prior therapy regimens and the subsequent salvage regimens that the patients received limit the impact of the detailed assessment of the type of therapy and its impact on outcomes. In summary, outcomes of adult patients with R/R CRLF2-rearranged B-ALL remain dismal with conventional chemotherapy but appear to improve with incorporation of novel targeted therapies. Allo-SCT in remission remains important and a subset of patients can achieve durable remission post allo-SCT. Larger prospective studies are needed to understand the optimal therapeutic regimen for these patients. Funding to Dr. Nitin Jain: Leukemia Lymphoma Society Career Development Award and MDACC P30 CA016672. Nitin Jain has received research funding from Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis, Carna Biosciences, Sana Biotechnology, Kisoji Biotechnology. Nitin Jain has received honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma, Ipsen, CareDX, MingSight, Novalgen. Remaining authors declare no relevant conflicts. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Baseline patient and disease characteristics Table S2. Distribution of therapies within each cohort Table S3. Characteristics of patients undergoing allogeneic stem cell transplant. Figure S1. Survival of patients based on response to therapy Figure S2. Impact of JAK2 mutation on survival Figure S3. Impact of JAK2 mutation on survival based on cohort Figure S4. Overall survival of all patients who underwent allogeneic stem-cell transplant. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.